Pulmonary hypertension (PH) is a devastating disease of diverse etiology that leads to progressive right heart failure and death. It has been proposed that an imbalance between vasoconstrictive and vasodilator mechanisms initiated by pulmonary endothelial dysfunction causes an increased pulmonary vascular remodeling, and fibrosis leading to right ventricular failure and PH. Based on evidence from the literature and our preliminary data, we propose that a balance between endothelial angiotensin converting enzyme (ACE) and ACE2 is critical in maintaining normal pulmonary vascular homeostasis. Thus, an imbalance in ACE/ACE2 is central in the initiation of pathophysiological events leading to PH. We hypothesize that increasing levels of ACE2 or its enzymatic product, Angiotensin-(1-7) [Ang-(1-7)], in the lungs would reverse endothelial dysfunction, decrease pulmonary vascular remodeling, improve right ventricular function and therefore protect and ameliorate or reverse PH. We propose the following aims to support or refute this hypothesis: Aim 1 will use two additional animal models of PH (hypoxia rat, and bone morphogenetic protein receptor 2, Bmpr2, conditional knockout mouse) to establish the concept that increases in pulmonary ACE2 or Ang-(1-7) would reverse PH. Aim 2 will test the hypothesis that a newly discovered ACE2 activator, DIZE, would reverse PH. In addition, we will investigate the mechanism of DIZE's actions on the pulmonary vessels. Aim 3 will investigate the hypothesis that local delivery of ACE2 or Ang-(1-7) by hematopoietic stem cells expressing these therapeutic genes will reverse PH. This multi-disciplinary and physiological genomic approach to investigate the hypothesis that the endothelial ACE/ACE2 is key to the PH pathophysiology is both novel and innovative. In addition, it will: (i) provide evidence that restoration of ACE/ACE2 imbalance in the pulmonary vasculature would reverse PH, and (ii) put us in an outstanding position to translate our hypothesis driven animal investigations into clinical phase trial for PH.